Anticoagulants are substances that prevent blood from clotting. They are commonly used during percutaneous coronary intervention (PCI) and other catherization techniques in order to reduce bleeding complications. One class of anticoagulants is direct thrombin inhibitors that disrupt the activity of thrombin, an important protein in the coagulation cascade. In particular, bivalirudin (ANGIOMAX®), which directly inhibits thrombin by specifically binding to both its catalytic site and to the anion-binding exosite, is regarded as a highly effective anticoagulant for use during catherization procedures.
Bivalirudin, also known as Hirulog-8, is a synthetic congener of the naturally occurring thrombin peptide inhibitor hirudin, which is found in the saliva of the medicinal leech Hirudo medicinalis. Hirudin consists of 65 amino acids, although shorter peptide segments have proven to be effective as thrombin inhibitors. U.S. Pat. No. 5,196,404 (incorporated herein by reference) discloses bivalirudin among these shorter peptides that demonstrate an anticoagulant activity. However, in contrast to hirudin, bivalirudin is a reversible inhibitor, which is ideal for temporary prevention of blood clotting during catherization procedures.
In light of the medical and therapeutic applications of bivalirudin, it is essential that the bivalirudin formulation maintains a high level of purity. The bivalirudin formulation is a compounded formulation containing bivalirudin, e.g., bivalirudin undergoes a compounding process following its synthesis so that it is usable and stable for medical and therapeutic applications.
Impurities such as Asp9-bivalirudin (deamidation of asparagine at position 9 of bivalirudin to aspartic acid) and D-Phe12-bivalirudin (isomerization of L-phenylalanine at position 12 of bivalirudin to the D-isomer) may be generated during the synthesis of bivalirudin. Consequently, processes for synthesizing bivalirudin have been developed to minimize the generation of impurities. However, impurities can also be produced during the compounding process, i.e., the process to generate a formulation of bivalirudin. It has been shown that various compounding processes can result in formulations that have up to 12% of Asp9-bivalirudin, which may affect product stability and shelf-life. Therefore, development of a compounding process for formulating bivalirudin that consistently generates formulations having low levels of impurities is desirable.
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